Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms

Autor(es)

Viana, Gustavo M. ^{[1, 2]} ; Priestman, David A. ^[3] ; Platt, Frances M. ^[3] ; Khan, Shaukat ^[4] ; Tomatsu, Shunji ^[4] ; Pshezhetsky, Alexey V. ^{[3, 1, 2]}

Afiliação do(s) autor(es)

^[1] CHU Ste Justine, Res Ctr, Div Med Genet, Montreal, PQ H3T 1C5 - Canada

^[2] Fed Univ Sao Paulo UNIFESP, Dept Biochem, BR-04044020 Sao Paulo, SP - Brazil

^[3] Univ Oxford, Dept Pharmacol, Oxford OX1 3SZ - England

^[4] Nemours Alfred I duPont Hosp Children, Wilmington, DE 19801 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL MEDICINE; v. 9, n. 2 FEB 2020.
• Citações Web of Science: 0

Resumo

Mucopolysaccharidoses (MPS) are the group of lysosomal storage disorders caused by deficiencies of enzymes involved in the stepwise degradation of glycosaminoglycans. To identify brain pathology common for neurological MPS, we conducted a comprehensive analysis of brain cortex tissues from post-mortem autopsy materials of eight patients affected with MPS I, II, IIIA, IIIC, and IIID, and age-matched controls. Frozen brain tissues were analyzed for the abundance of glycosaminoglycans (heparan, dermatan, and keratan sulfates) by LC-MS/MS, glycosphingolipids by normal phase HPLC, and presence of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor superfamily member 10 (TNFSF10) by Western blotting. Fixed tissues were stained for the markers for microgliosis, astrogliosis, misfolded proteins, impaired autophagy, and GM2 ganglioside. Our results demonstrate that increase of heparan sulfate, decrease of keratan sulfate, and storage of simple monosialogangliosides 2 and 3 (GM2 and GM3) as well as the neutral glycosphingolipid, LacCer, together with neuroinflammation and neuronal accumulation of misfolded proteins are the hallmarks of brain pathology in MPS patients. These biomarkers are similar to those reported in the corresponding mouse models, suggesting that the pathological mechanism is common for all neurological MPS in humans and mice. (AU)

• Processo FAPESP: 18/17003-6 - Glicosaminoglicanos como ativadores de neurodegeneração na MPS IIIC e Doença de Alzheimer
• Beneficiário: Gustavo Monteiro Viana
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado